Minneapolis, Minnesota -
It is known that subsequent to cardiac infarction, various cytokines are produced by the injured myocardium that mobilize endogenous stem cells from the bone marrow into systemic circulation, and specifically "calling" them to home to the ischemic tissue. Unfortunately, this process occurs only to a small extent and full repair of the myocardium after injury seldom occurs (Vandervelde et al. Signaling factors in stem cell-mediated repair of infarcted myocardium. J Mol Cell Cardiol. 2005 Aug;39(2):363-76).
One of the major factors secreted by myocardium as a result of ischemia is stromal derived growth factor-1 (SDF-1). In fact, it is known that mice that are genetically manipulated to lack SDF-1, have a diminished reparative potential post-infarct (Abbott et al. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation. 2004 Nov 23;110(21):3300-5).
Interestingly, SDF-1 is one of the major cytokines that specifically calls in hematopoietic stem cells to the bone marrow after they are administered systemically. Accordingly, one possible method of specifically induce the homing of stem cells into a damaged tissue may be to artifically introduce exogenous SDF-1 in the area which is in need of repair.
In a recent study (Zhang et al. Controlled Release of Stromal Cell-Derived Factor-1alpha In situ Increases C-kit+ Cell Homing to the Infarcted Heart. Tissue Eng. 2007 Feb 22) this was exactly what was done!
The investigators developed a controlled release SDF-1 comprised of pegylated fibrinogen covalently bound to SDF-1. The SDF-1-fibrinogen was converted to a "SDF-1-fibrin patch" by addition of thrombin. Fibrin patches, or fibrin glue are commonly used in surgery since that can easily be placed on blood vessels to stop bleeding, as well as injected into various tissues.
When this "SDF-1-fibrin patch" was placed on the surface of an infarcted mouse heart (achieved by LAD coronary artery ligation), a significant increase in stem cells (defined as c-kit positive) was observed at 2 weeks in the treated but not fibrin patch alone control mice. Furthermore, at 28 days, mice in the experimental group had a statistically significant higher left ventricular ejection fraction as control.
This paper demonstrates a powerful technique for specific chemotaxis of stem cells. These methods would potentially achieve great synergy when used with stem cell mobilizing agents.
IP covering this concept appears in US patent application # 20050118144 to Zhang, Jianyi (Roseville, MN, US).